The global prevalence of obesity is increasing epidemically. Obesity causes an array of health problems, reduces life expectancy, and costs over US$100 billion annually. More than a quarter of the population suffers from an aggregation of co-morbidities, including obesity, atherosclerosis, insulin resistance, dyslipidemias, coagulapathies, hypertension, and a pro-inflammatory state known as the metabolic syndrome. Patients with metabolic syndrome have high risk of atherosclerosis as well as type 2 diabetes and other health problems. Like obesity, atherosclerosis has very limited therapeutic options.
Atherosclerosis is the leading cause of death in the United States. At the core of this syndrome is the dysregulation of lipid metabolism and aberrant inflammatory responses. Although mechanistic roles for fatty acids have been put forward in the formation of obesity and diabetes by modifying glucose and lipid metabolism as well as inflammatory cascades, little is known about the mechanisms that link fatty acids or other lipid signals to inflammatory responses and the formation of atherosclerotic lesions. The biology of fatty acid binding proteins (FABPs) in several mouse models with targeted mutations in adipocyte/macrophage isoforms of these proteins has been investigated. Although serum fatty acid levels are not reduced in these FABP-deficient models, they are strikingly and paradoxically protected from obesity, insulin resistance, type 2 diabetes, fatty liver disease and atherosclerosis. This phenotype emphasizes the fact that total fatty acids may not be the primary pathogenic indicator, and that individual fatty acid or metabolite action at the intracellular level and the specific responses evoked by these signals are more relevant to the pathophysiology and outcomes of atherosclerotic disease than parameters classically measured.
Lipids and lipid signals are critical in the integration of metabolic and integration of metabolic and inflammatory response systems and consequently play significant parts in the pathogenesis of a cluster of chronic metabolic diseases, including type 2 diabetes, fatty liver disease and atherosclerosis. However, how lipids couple to target signaling pathways or metabolic processes and how their intracellular trafficking is regulated are poorly understood. Cytoplasmic fatty-acid-binding proteins (FABPs) are a family of 14-15-kDa proteins that bind with high affinity to hydrophobic ligands such as saturated and unsaturated long-chain fatty acids and eicosanoids such as hydroxyeicosatetra-enoic acid, leukotrienes and prostaglandins. The adipocyte FABP, aP2 (FABP4), is highly expressed in adipocytes and regulated by peroxisome-proliferator-activated receptor-γ (PPAR γ) agonists, insulin and fatty acids.
Impaired insulin action at its target tissues, a phenomenon termed insulin resistance, is typical in obesity, type 2 diabetes, and associated atherosclerosis but also occurs during inflammatory and neoplastic processes. The development of insulin resistance has been linked to augmented availability of lipids and other nutrients. Specifically, plasma concentrations of free fatty acids (FFAs) are elevated in insulin resistance and even predict type 2 diabetes. Over past years, evidence has accumulated that FFAs induce insulin resistance by raising intracellular lipid metabolites.
The concentrations of FFAs can increase either in the circulating blood due to high-fat diet and release by adipocytes or within cells consequent to lipolysis or de novo synthesis. FFAs traffic through the body mainly while bound to fatty acid transport proteins, whereas fatty acid-binding proteins (FABPs) regulate their intracellular fate. In this regard, FABPs include, for example FABP2, FABP3, FABP4, FABP5, etc. Specifically, the adipocyte-specific isoform (FABP4, A-FABP, ALBP or aP2) has gained attention for its proposed role in metabolic disorders and atherosclerosis.
There is a need for additional ways of treating diseases associated metabolic syndrome such as, for example, dyslipedemia, obesity and diabetes (e.g., Type 2 diabetes).
Furthermore, Fatty acid binding proteins integrate metabolic and immune responses and link the inflammatory and lipid-mediated pathways that are critical in the metabolic syndrome.
The link between FABPs and the various diseases stated above is discussed by Roden et al, Cell Metabolism (2007) 6, pp. 89-91; Furuhashi et al, Nature (2007) 447, pp. 959-965; and Makowski et al, Current Opinion Lipidology (2005) 16, pp. 543-547.
A need exits in the art, however, for FABP inhibitors, especially FABP4 inhibitors, that have efficacy for the treatment of metabolic disorders such as, for example, obesity, type II diabetes mellitus and metabolic syndrome.
A need exits in the art, however, for FABP inhibitors, especially FABP5 inhibitors, that have efficacy for the treatment of metabolic disorders such as, for example, obesity, type II diabetes mellitus and metabolic syndrome.
A need exits in the art, however, for FABP inhibitors, especially FABP3 inhibitors, that have efficacy for the treatment of metabolic disorders such as, for example, obesity, type II diabetes mellitus and metabolic syndrome.
A need exits in the art also for dual FABP inhibitors that have efficacy for the treatment and/or prevention of cardiovascular conditions.